Optic Neuritis, marked by idiopathic, sudden inflammation of the optic nerve (ON), is the most commonly presenting symptom of MS. An estimated 50% of MS patients have a history of optic neuritis, which often resolves with time, and there are no effective treatments. However, its mere presence can be a signature of the early stages of MS, which, even with resolved clinical symptoms, could represent devastating axonal and myelin pathology. Our first hypothesis is that assessment of the optic nerve using MRI methods sensitive to axonal and myelin integrity can provide quantitative information about microscopic tissue changes in the ON of patients with MS. Our second hypothesis is that these metrics can be related to measures of the retinal nerve fiber layer (optical coherence tomography [OCT]) thickness, and visual dysfunction (low contrast visual acuity). Our overall goal is to devise and validate a multi-modality, myelin and axonal sensitive set of MR metrics for routine application in the clinic to study overt and silent ON damage in MS patients with and without history of optic neuritis. To accomplish our goal, we have set the following specific Aims. Aim 1: To develop Diffusion Tensor Imaging (DTI) and Magnetization Transfer (MT) imaging for the ON, a structure whose size, constant motion and proximity to the maxillary sinuses (increased magnetic susceptibility artifacts) has hampered DTI and MT methods. The reproducibility of the derived DTI and MT metrics will be assessed in healthy controls. Aim 2: To assess the ability of the DTI and MT schemes to detect pathology in patients with MS who have history of optic neuritis. Patient data will be compared with the healthy volunteer data obtained in AIM 1, and the sensitivity and specificity for ON damage will be assessed. Aim 3: To relate MT and DTI-derived metrics of the ON in MS patents with and without history of optic neuritis to 1) retinal nerve fiber layer thickness as determined by OCT and 2) low-contrast visual acuity assessed in the clinic. RELEVANCE: It is known that 17-20% of patients who present with optic neuritis eventually develop MS. The relevance is that quantitative diffusion and magnetization transfer MRI evaluation of the microstructure of the optic nerve (ON) in MS with or without history of optic neuritis may provide an earlier biomarker for MS and the evolution of MS. These methods should be applicable to other ON pathologies, and other difficult CNS tissues outside the brain.